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Investigating multistep continuous flow processes using diazonium salts

Schotten, Christiane 2018. Investigating multistep continuous flow processes using diazonium salts. PhD Thesis, Cardiff University.
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Abstract

This thesis describes the investigation of continuous flow processes that incorporate the generation and use of diazonium salts. In this manner, processes for the preparation of triazenes, indoles and acridones have been developed. Diazonium salts are potentially unstable and hazardous and have to be handled with care. The use of continuous flow processes enables the safe synthesis avoiding accumulation of large quantities. This is due to the possibility to intercept intermediates at a precise point in time within a closed system. Diazonium salts were prepared via in situ diazotization of anilines with isoamylnitrite. Triazenes were formed via the interception of diazonium salts with secondary amines. The process had to be carefully developed to avoid clogging and fouling of the reactor. 26 examples have been prepared. The thermal behavior of 13 triazenes has been compared to their corresponding tetrafluoroborate diazonium salts, which has shown they are significantly more stable. In addition, VT NMR analysis has been performed to explore restricted rotation around the triazene bond. Further developments have found that indoles can be prepared via reduction of diazonium salts to their corresponding hydrazine with ascorbic acid and subsequent Fischer indole reaction in a microwave reactor. The use of such a hybrid, machine assisted approach has enabled the formation of a library of indoles. In this manner, 33 examples have been synthesised including the drug Zolmitriptan and nine of its analogues. The formation of acridones from benzyne and anthranilates has been investigated. Benzyne was prepared via the thermal decomposition of benzenediazonium-2-carboxylate. The compound decomposes above ambient temperatures and is known to be explosive when dry. The formation of benzyne has been investigated using the Diels- Alder reaction with furan as a model reaction and then conditions were applied to a range of substrates to investigate the scope. Problems with solubility of starting materials, diazonium salts and products were encountered and partially solved through the screening of different solvents. Finally, an exothermic reaction was investigated under continuous flow reactions. Commercially available thermocouples and in line NMR analysis were used to facilitate process optimisation. The exothermic reaction explored was the reduction of TMSCF3 to TMSCF2H with NaBH4. The exotherm was monitored using external, commercially available thermocouples to realise the development of a safe reaction regime. The incorporation of in situ NMR measurements has allowed realtime assessment of reaction conversion as a correlation to the exotherm. With the combined monitoring approaches a safe scale up process has been established. A hybrid flow - batch approach was used to scale up the reaction and increase the space time yield compared to the previously reported batch reaction.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 31 July 2018
Last Modified: 14 Apr 2021 11:57
URI: http://orca.cardiff.ac.uk/id/eprint/113812

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